Selection and analysis of ions and charged aerosols by means of their physical properties is very useful for many applications including chemical analysis, environmental analysis, for the production of small particles of controlled size, for nano-technological applications and related scientific studies, etc. The present invention can be used with charged particles suspended in a gas, where the term charged particles should by understood in its broadest sense as particles of any size whose net electrical charge is different from zero. However, for simplicity, charged particles and ions will all be referred to as ions.
Any apparatus used to select, analyze or measure is characterized by its sensitivity and its resolution. Analyzers are used to measure key properties of the substances under study. The sensitivity refers to the minimum amount of substance that the apparatus is able to sense or work with, while the resolution refers to the smallest difference in such key properties that the apparatus can distinguish. A widely used definition of the Resolution is based on the Full With at Half Maximum algorithm (FWHM). Applying this definition to a Gaussian peak yields
      R    gauss    =      μ          σ      ·      2      ·                                    2            ·            ln                    ⁢                                          ⁢          2                    where μ and σ are, respectively, the mean and the standard deviation.
Among the most commonly used ion analyzers, Mass Spectrometers, also termed MS, produce information very relevant to the chemical structure and composition of ions with very high resolution and very high sensitivity. There are different types of mass spectrometers, but they all have in common that the ions are separated according to mass/charge due to the mass/charge dependence of their motion when subjected to specific electric and magnetic fields in vacuum. The present invention can be coupled to an MS trough a simplified version of an API system. The API interface (Atmospheric Pressure Interface) requires some more detail that will later provide a background for the present invention. The MS inlet is most often a small orifice in a plate or the bore of a capillary, through which gas and ions are sampled at sonic speed into the vacuum system of the MS. To prevent neutral vapors from entering the MS, a counterflow dry gas is sometimes interposed between the electrospray and the atmospheric inlet of the MS. Ions are pushed forward by the electric field while neutral species and droplets are dragged away by the counterflow. See Refs [1] [2], and U.S. Pat. No. 4,531,056.
Complex samples produce very complex spectra difficult to evaluate. Big proteins are also difficult to analyze by simple MS techniques. Either because the high amount of different compounds produce overlapped peaks in the mass spectrum or because there are many isomers and many charged states for each mass, the spectrum produced by simple MS when the amount of different substances is very complicated tends to be difficult to interpret if not impossible. Tandem analysis techniques are a very powerful tool which allows unfolding a complex spectrum over more than one variable.
Ions can also be separated according to their electric drift velocity in a bath gas. More specifically, ions can be selected or characterized by their electrical Mobility Z, defined as the ratio of electric velocity to electric field. Note that, at atmospheric pressure, the effect of magnetic force is usually negligible because ionic speed is limited and the effect of electric fields is substantially stronger than the effect of state of the art magnetic fields. Using the definition of mobility, the electric velocity of an ion is: VE=Z·Ē  (1)where VE stands for the electric velocity of the ions induced by the electric field, and E stands for the electric field. And the total velocity of the ion is the sum of the electric velocity plus the fluid velocity:
                                                        ⅆ                              X                →                                                    ⅆ              t                                -                                    V              →                        E                    +                                    V              →                        f                          =                              Z            ·                          E              →                                +                                    V              →                        f                                              (        2        )            where Vf stands for the fluid velocity, X stands for the position of the ion, and t is the time.
The mass of an ion is a very specific and useful information, since it is directly related to its composition. The mobility is not related to the structure of the ion so directly, but it still gives some information on its structure. Basic kinetic theory states that mobility is inversely proportional to the collision cross section and the square root of the reduced mass of the ion and the gas molecules. Heavier molecules usually have lower mobility. Isomers having identical masses can still be differentiated according to their mobility when they have different cross sections. Various methods have been used to separate ions according to their electrical mobility.
IMS: Ion Mobility Spectrometry consist of a pulsed gate, which produces packets of ions, followed by a drift tube, in which an axial steady electric field parallel to the drift tube pushes the ions along the axis of the drift tube towards a detector at the end of the drift tube. The gas is usually at rest and the fluid velocity is usually negligible compared to the electric velocity. When the gate produces a packet of ions at time t=t0, the different ions enter simultaneously in the drift tube. Once in the drift tube, each different type of ion drifts at a different electric velocity. Therefore, the original packet of ions is separated into different packet of ions according to their mobility. Ions reach the sensor at time
                    t        =                              t            0                    +                                    l                              Z                ·                E                                      .                                                          More mobile ions travel faster and reach the sensor before less mobile ions which travel slower. After each pulse of the gate, the IMS produces a full spectrum of the sample. As ions travel along the drift tube, the different packets of ions of the same mobility are also broadened by Brownian diffusion which limits the resolution achievable by IMS techniques. The resolution achieved in a drift tube depends on the length of the drift tube, but typical resolutions can be around 100. Resolution in an IMS spectrum is defined as RIMS=τ/δτ, where ‘τ’ is the time required to travel along the drift tube and ‘dτ’ is the duration of the signal produced by the packet of ions. The time τ is equal to τ=l/VE, where l is the length of the drift tube, while δτ=σ/VE where σ is the size of the broadened packet of ions. On the other hand, σ is given by: σ=√{square root over (2·D·τ)}, where D is the diffusion coefficient of the ion in the gas. Finally, using Einstein equation, which states that
      D    =          Z      ·                                    k            B                    ·          T                e              ,where kB is the Boltzmann constant and T is the temperature of the gas, and e is the charge of the ion, a first approximation to the IMS resolution is:
                              R          IMS                =                                            l              ·              E              ·              e                                      2              ·                              k                B                            ·              T                                                          (        3        )            
Numerous methods have been used to increase the resolution and the duty cycle of IMS instruments. Of particular relevance to the present invention have been various attempts to do so by synchronization of various gates or various electric fields applied in various regions separated by gates or electrodes subject to sequences of voltages:
Resolution can be increased by increasing the applied high voltage l·E But, too high voltages can be difficult to produce, they are difficult to handle and, in any case, too high voltages can be dangerous. A solution to this problem is using a sequence of drift tubes in which they are switched on and off sequentially. This type of configuration is useful to study a narrow range of mobilities. Only the region containing the ions is switched on. In this way, ions under study are always subjected to a strong electric field, but the total voltage required remains limited. By doing this, very high resolutions can be achieved. The problem of this configuration is that only a very narrow range of mobility can be studied at a time. Only those ions hose drift time is synchronized with the on/off switching sequence can pass the filter. For some applications requiring a narrow band mobility filter this is not a problem. In fact, IMS devices have also been used as narrow band mobility filters by including a pulsed gate at the end of the drift tube. Only those ions hose drift time is synchronized with the offset time between the inlet and outlet gates can pass the IMS. Sequences of drift tubes and pulsed gates have also been used. However, these configurations produce a very low duty cycle, very poor transmission, and dilution of the ions when diffusion of the packet of ions is not compensated for.
The length of the IMS is also limited by the Brownian broadening of the ion packets in the transversal direction because ions are dispersed transversally, diluted, and eventually, they can be lost in the inner walls of the drift tube. Transversal diffusion can be counterbalanced by means of ion funnels. See U.S. Pat. No. 6,107,628. Various drift tubes can be coupled by synchronizing their gates producing a sequence of IMS to increase resolution of the mobility-filtered packets of ions. In order to counteract the dilution of the packets due to long drift times in long sequences, ion funnels can be also intercalated between the drift tube stages. This configuration also filters ions by synchronization between the residence time of an ion in the analyzer and the gates aperture offset time or the drifts tube switching on and off period. An interesting configuration of a sequence of gates, drift tubes, and ion funnels, was presented by D. Clemmer and colleagues, and termed High-Resolution Ion Cyclotron Mobility. See Ref [3]. In this configuration, ions are driven through a closed loop sequence of four drift tubes and four ion funnels. As the total electric potential difference has to be zero along a closed loop, they are forced to switch two of the drift tubes with an opposite field that pushes the ions backwards. This problem is easily overcome by using only two of the four drift tubes at a time and by changing the polarity of the system at a given frequency when the packs of selected ions are within the ions funnels. No gates are required in the loop because the two opposing drift tubes act themselves as gates. When the polarity changes in a drift tube, lagging ions, that could not reach the ion funnel in time, are chopped from the pack of ions. While overspeeding ions are stopped when they try to leave the ion funnel too early before the subsequent drift tube changes its polarity to push the ions favorably upwards.
Clemmer et al. explain that they accomplish filtration by changing the drift field at a frequency that is resonant with the ion's drift time through each region. Note that the selected ions are only affected by the favorable part of the cycle of the varying electric field that pushes the ions upwards in each stage of the cyclotron, while other ions are stopped by the unfavorable electric field. Selected ions are thus always subjected to a steady electric field as if they where traveling through a multistage drift tube with steady electric fields and far more than four drift tubes, ion funnels and gates. As a result, the output of filtered ions is pulsed as if a very long sequence of IMS was used to filter by means of gate synchronization.
IMS have been coupled with mass spectrometers, gas chromatography (GC), and liquid chromatography (LC). The IMS-MS technique produces tandem mass and mobility data which, as mentioned earlier, is useful for the analysis of complex samples and big molecules. Nevertheless, coupling an IMS with most commercial MS instruments is nontrivial because the IMS output is pulsed and generally takes place at low pressure, while most MS systems used in combination to LC sample steady (rather than pulsed) atmospheric pressure gases.
Two other devices have been used to separate ions carried in a gas, both producing steady beams of selected ions. These instruments are therefore more readily coupled with atmospheric pressure ionization mass spectrometers than drift time IMS. DMA: The first is the Differential Mobility Analyzers (DMA). In a DMA, a steady electric field and a steady laminar fluid velocity field are used. Different configurations have been proposed; see PCT/US2004/005133 U.S. Pat. Nos. 5,596,136 and 5,606,112 and Ref [4]. In the most common configuration, the flow moves in a channel where a perpendicular electric field is produced between two walls of the DMA channel. The ions are introduced continuously in the DMA through an inlet slit. The ions exhibit oblique trajectories as their velocity is the sum of the fluid velocity in one direction and the electric velocity in a different direction. According to their mobility, different ions have different trajectories. Only those ions within the selected narrow range of mobilities reach the DMA exit slit. This happens for a given fluid to electric velocity ratio which depends on the exact geometry of the DMA. A main difference between DMA and IMS is that the DMA produces spatial separation rather than time separation. The DMA is a narrow band filter, rather than a spectrometer. Once the fluid velocity is fixed, the filtered mobility can be selected by tuning the high voltage responsible for the electric field. Higher mobility ions require weaker electric fields while low mobility ions require stronger electric fields. Although the DMA is a narrow band filter, it is scannable, and therefore it can produce spectra. There are many types of DMA, cylindrical DMA have been widely used for the analysis of aerosols. However, it is difficult to access their inlet and outlet slits. For this reason it is difficult to couple cylindrical DMA with MS. Planar DMAs have more accessible inlet and outlet slits and have been coupled to several MS to produce two dimensional Mobility-Mass data. The main advantage of DMA-MS versus IMS-MS technique is that, once tuned at the mobility of interest, the DMA produces a steady flow of ions with a 100% duty cycle. Transmission and sensitivity is therefore much higher and synchronization with a MS is much simpler. See U.S. Pat. Nos. 5,869,831 and 5,936,242, and U.S. patent application Ser. No. 11/786/688 (PCT/EP2008/053762). The resolution achievable by a DMA is also limited by Brownian diffusion, but there are other factors affecting DMA resolution. Some details on the resolution of the DMA are required to provide the background of the present invention.
DMA resolution: If one assumes that the flow is perfectly laminar, the resolution in a DMA is limited by the Brownian diffusion and by the finite flow of ions. The limit given by Brownian diffusion can be broadly estimated as the characteristic length of the DMA channel ‘L’ divided by the diffusion broadening length given by σr=√{square root over (2·D·τ)}, where D is the diffusion coefficient of the ions in the gas, and τ is the time spent by the ions in the DMA channel. On the other hand, at a given geometry and a given fluid velocity, the time spent by the ions in the DMA channel can also be broadly estimated as τ=L/Vf. Joining the expressions for σ and τ, and the definition of the Reynolds number, yields a first rough expression for the resolution limit due to diffusion:
                              R          D                =                                                            L                ·                                  V                  f                                                            2                ·                D                                              =                                                                      R                  e                                ·                v                                            2                ·                D                                                                        (        4        )            where v is the kinematic viscosity of the drift gas. Equation 4 implies that the resolution increases with the Reynolds of the gas velocity field. The main problem arising in DMA is that, increasing the Reynolds to reduce diffusion effects, the flow of gas becomes unstable and resolution is spoiled by turbulence. DMA achieves satisfactory resolutions at low Reynolds that guarantee laminar flows when the diffusion coefficient D is low. Although it is difficult to achieve laminar flows at high Reynolds, a careful design can overcome this type of limitations. For instance, Martinez Lozano et al. have measured record resolutions above 100 [1/FWHM] for small ions of Tetra Heptil Ammonium Bromide (THABr+) on a cylindrical DMA, and J. Rus and J. Fernandez de la Mora have made planar DMA coupled to several MS with which they have measured record resolutions up to 80 for the same THABr+ ion.
These relatively high resolving powers are not easy to match, as the resolution of DMAs is strongly limited by turbulence, compressibility effects limiting the maximum velocity achievable, and sound pressure waves traveling upstream the DMA channel. Another problem regarding the DMA operation is that the pump required to produce the fast fluid flow in the DMA channel limits its operating temperature range and also hinders miniaturization. The DMA-MS technique also has the problem that it is difficult to deactivate the DMA and work in MS-only mode because there is an important offset between inlet and outlet slits.
FAIMS: Field Asymmetric Ion Mobility Spectrometry (FAIMS) is an alternative technique that, as the DMA, also separates ions geometrically rather than in time and, therefore, it also produces a continuous flow of selected ions with a 100% duty cycle. Moreover, FAIMS does not require a strong fluid velocity field, FAIMS has been successfully miniaturized, it has been successfully coupled to LC, GC and MS and, when coupled to an MS inlet, it is easy to deactivate and work in MS-only mode. FAIMS separates ions steadily in space according to weak nonlinearities associated to the slight dependence of their mobility on the strength of the electric field. In practice, mean ion trajectories are composed by the steady influence of a long lasting weak electric field (usually referred to as steady compensation voltage) and the small displacements due to many short opposed pulses of intense electric fields for which the ion mobility differs from that produced by the weak electric field. FAIMS therefore does not provide clearly interpretable structural information, as it separates not according to mobility, but according to slight nonlinearities in the mobility arising at high fields. See U.S. Pat. No. 5,420,424 and U.S. Pat. No. 6,806,466.
The main limitations of FAIMS are the need for a complex high voltage and high frequency (around 200 KHz) power supply, and, especially, its relatively low resolution compared to what can be achieved by drift time IMS or a DMA. Its main advantage is that, like the DMA, it can be coupled with many mass spectrometers having an atmospheric pressure interface.
In conclusion, there are presently no known solution to the related problem of achieving (i) a continuous, non-pulsed, narrow band ion mobility filter separating according to electrical mobility rather than according the non linear behavior of the mobility; (ii) operating at low flow Reynolds number (Re<5000) such that laminar and stable fluid movement is assured; (iii) achieving resolution higher than 40; (iv) being easy to couple to other analyzer equipments such as mass spectrometers (MS); (v) being easy to sidestep when coupled with other analyzer equipments such as MS in order to permit switching from Mobility-Mass measuring mode to simple Mass measuring mode.